Professor Danielle Dube
Professor Danielle Dube
Department of Chemistry
Bowdoin College
Host: Professor Erin Carlson
Chemical tools to discover and target glycoproteins on pathogenic bacteria
The bacterial cell wall is a quintessential drug target due to its critical role in colonization of the host, pathogen survival, and immune evasion. The dense cell wall glycocalyx contains distinctive monosaccharides that are absent from human cells, and proper assembly of monosaccharides into higher-order glycans is critical for bacterial fitness and pathogenesis. However, the systematic study and inhibition of bacterial glycosylation enzymes remains challenging. Bacteria produce glycans containing rare deoxy amino sugars refractory to traditional glycan analysis, complicating the study of bacterial glycans and the creation of glycosylation inhibitors. Thus, the development of chemical tools that label bacterial glycans is a crucial step toward discovering and targeting these biomolecules. This seminar will describe how metabolic glycan labeling – which exploits carbohydrate biosynthetic pathways to install unnatural sugars bearing chemical reporters into cellular glycans – has facilitated the studying and targeting of glycoproteins on pathogenic bacteria. In particular, I will describe how this method enabled the discovery of glycoproteins in the gastric pathogen Helicobacter pylori, our recent expansion of this methodology to a range of pathogenic and symbiotic bacterial species, and our development of metabolic inhibitors of glycan biosynthesis to inactivate bacterial pathogens. This work sets the stage to refine our knowledge of the glycan repertoire in diverse bacteria and to disarm bacterial based on their distinctive glycan coating, ultimately providing a platform for the development of novel, narrow-spectrum antibiotics to treat infectious disease.
Professor Dube
Recent efforts in Professor Dube's laboratory have focused on the pathogenic bacterium Helicobacter pylori, which is the leading cause of duodenal ulcers and stomach cancer worldwide. Researchers are taking a metabolic labeling-based approach to study H. pylori sugar-coated proteins and to target H. pylori based on its unique sugars. They are pursuing a series of parallel projects that seek to:
- structurally characterize H. pylori’s distinctive sugars;
- explore the role of these sugars in causing disease;
- identify the genes responsible for their biosynthesis;
- validate H. pylori’s sugars as potential drug targets;
- create inhibitors of bacterial glycan biosynthesis; and
- develop targeted antibiotics that, like smart-bombs or guided missiles, seek out and react with H. pylori’s sugars, leading to selective destruction of H. pylori cells without destroying beneficial bacteria
